1. Field of the Invention
This invention pertains to substituted .beta. amino acid derivatives which inhibit platelet aggregation.
2. Related Art
Fibrinogen is a glycoprotein present as a normal component of blood plasma. It participates in platelet aggregation and fibrin formation in the blood clotting mechanism.
Platelets are cellular elements found in whole blood which also participate in blood coagulation. Fibrinogen binding to platelets is important to normal platelet function in the blood coagulation mechanism. When a blood vessel receives an injury, the platelets binding to fibrinogen will initiate aggregation and form a thrombus. Interaction of fibrinogen with platelets occurs through a membrane glycoprotein complex, known as gpIIb/IIIa; this is an important feature of tile platelet function. Inhibitors of this interaction are useful in modulating or preventing platelet thrombus formation.
It is also known that another large glycoprotein named fibronectin, which is a major extracellular matrix protein, interacts with fibrinogen and fibrin, and with other structural molecules such as actin, collagen and proteoglycans. Various relatively large polypeptide fragments in the cell-binding domain of fibronectin have been found to have cell-attachment activity. (See U.S. Pat. Nos. 4,517,686; 4,589,881; and 4,661,111). Certain relatively short peptide fragments from the same molecule were found to promote cell attachment to a substrate when immobilized on the substrate or to inhibit attachment when in a solubilized or suspended form. (See U.S. Pat. Nos. 4,578,079 and 4,614,517).
In U.S. Pat. No. 4,683,291, inhibition of platelet function is disclosed with synthetic peptides designed to be high affinity antagonists of fibrinogen binding to platelets. U.S. Pat. No. 4,857,508 discloses tetrapeptides having utility as inhibitors of platelet aggregation.
Other synthetic peptides and their use as inhibitors of fibrinogen binding to platelets are disclosed by Koczewiak et al., Biochem. 23, 1767-1774 (1984); Plow et al., Proc. Natl. Acad. Sci. 82, 8057-8061 (1985); Ruggeri et al., Ibid. 83, 5708-5712 (1986); Ginsberg et al., J. Biol. Chem. 260 (7), 3931-3936 (1985); Haverstick et al., Blood 66 (4), 946-952 (1985); and Ruoslahti and Pierschbacher, Science 238, 491-497 (1987). Still other such inhibitory peptides are disclosed in EP Patent Applications 275,748 and 298,820.
U.S. Pat. No. 4,879,313 discloses compounds useful as inhibitors of platelet aggregation having the formula: ##STR1## wherein
x=6 to 10,
y=0 to 4,
Z=H, COOH, CONH2 or Cl-6 alkyl,
Ar=phenyl, biphenyl or naphthyl, each substituted with 1 to 3 methoxy groups, or an unsubstituted phenyl, biphenyl, naphthyl, pyridyl or thienyl group, and PA1 Asp=aspartic acid residue. PA1 1. ester (COOR) PA1 Wherein R can be lower alkyl, alicyclic hydrocarbon radical or aromatic hydrocarbon radical, PA1 2. amide (CONR'R") PA1 Wherein R' and R" are independently selected from the group consisting of hydrogen, linear or alicyclic hydrocarbon, aromatic hydrocarbon radical, hydroxy or alkoxy radical, PA1 CHCl.sub.3 =chloroform PA1 DMF=dimethylformamide PA1 DMSO=dimethylsulfoxide PA1 g=gram PA1 MeOH=methanol PA1 min=minute PA1 h=hour PA1 mol=mole PA1 mmol=mmole PA1 MW=molecular weight PA1 TLC=thin layer chromatography PA1 NMM=N-methylmorpholine PA1 RPHPLC=Reverse Phase High Pressure Liquid Chromatography PA1 TDA-1=Tris[2-(2-methoxyethoxy)ethyl]amine PA1 PTC=Phase Transfer Catalysis
European Patent Application 372,486 discloses N-acyl .beta. amino acid derivatives of the formula: ##STR2## and their salts. Said compounds are useful for inhibiting platelet aggregation in the treatment of thrombosis, stroke, myocardial infarction, inflammation and arteriosclerosis, and for inhibiting metastasis.
European Patent Application 381,033 discloses amidino or guanidinoaryl substituted alkanoic acid derivatives useful for the treatment of thrombosis, apoplexy, cardiac infarction, inflammation, arteriosclerosis and tumors.
European Patent Application 445,796 discloses Acetic Acid derivatives useful as a ligand for adhesive proteins on blood platelet. As such these compounds are useful to modulate and/or inhibit platelet aggregation.